@article{SchneiderPliushchElHajjetal.2010,
  author    = {Schneider, Eberhard and Pliushch, Galyna and El Hajj, Nady and Galetzka, Danuta and Puhl, Alexander and Schorsch, Martin and Frauenknecht, Katrin and Riepert, Thomas and Tresch, Achim and Mueller, Annette M. and Coerdt, Wiltrud and Zechner, Ulrich and Haaf, Thomas},
  title     = {Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68371},
  year      = {2010},
  abstract  = {DNA methylation is an epigenetic modification that plays an important role in gene regulation. It can be influenced by stochastic events, environmental factors and developmental programs. However, little is known about the natural variation of genespecific methylation patterns. In this study, we performed quantitative methylation analyses of six differentially methylated imprinted genes (H19, MEG3, LIT1, NESP55, PEG3 and SNRPN), one hypermethylated pluripotency gene (OCT4) and one hypomethylated tumor suppressor gene (APC) in chorionic villus, fetal and adult cortex, and adult blood samples. Both average methylation level and range of methylation variation depended on the gene locus, tissue type and/or developmental stage. We found considerable variability of functionally important methylation patterns among unrelated healthy individuals and a trend toward more similar methylation levels in monozygotic twins than in dizygotic twins. Imprinted genes showed relatively little methylation changes associated with aging in individuals who are >25 years. The relative differences in methylation among neighboring CpGs in the generally hypomethylated APC promoter may not only reflect stochastic fluctuations but also depend on the tissue type. Our results are consistent with the view that most methylation variation may arise after fertilization, leading to epigenetic mosaicism.},
  subject      = {Medizin},
  language  = {en}
}
@article{HansmannPliushchLeubneretal.2012,
  author    = {Hansmann, Tamara and Pliushch, Galyna and Leubner, Monika and Kroll, Patricia and Endt, Daniela and Gehrig, Andrea and Preisler-Adams, Sabine and Wieacker, Peter and Haaf, Thomas},
  title     = {Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer},
  series = {Human Molecular Genetics},
  volume    = {21},
  journal   = {Human Molecular Genetics},
  number    = {21},
  doi       = {10.1093/hmg/dds308},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125673},
  pages     = {4669-4679},
  year      = {2012},
  abstract  = {Genetic defects in breast cancer (BC) susceptibility genes, most importantly BRCA1 and BRCA2, account for ∼40\% of hereditary BC and ovarian cancer (OC). Little is known about the contribution of constitutive (soma-wide) epimutations to the remaining cases. We developed bisulfite pyrosequencing assays to screen >600 affected BRCA1/BRCA2 mutation-negative patients from the German Consortium for Hereditary Breast and Ovarian Cancer for constitutive hypermethylation of ATM, BRCA1, BRCA2, RAD51C, PTEN and TP53 in blood cells. In a second step, patients with ≥6\% promoter methylation were analyzed by bisulfite plasmid sequencing to demonstrate the presence of hypermethylated alleles (epimutations), indicative of epigenetic gene silencing. Altogether we identified nine (1.4\%) patients with constitutive BRCA1 and three (0.5\%) with RAD51C hypermethylation. Epimutations were found in both sporadic cases, in particular in 2 (5.5\%) of 37 patients with early-onset BC, and familial cases, in particular 4 (10\%) of 39 patients with OC. Hypermethylation was always confined to one of the two parental alleles in a subset (12-40\%) of the analyzed cells. Because epimutations occurred in cell types from different embryonal layers, they most likely originated in single cells during early somatic development. We propose that analogous to germline genetic mutations constitutive epimutations may serve as the first hit of tumor development. Because the role of constitutive epimutations in cancer development is likely to be largely underestimated, future strategies for effective testing of susceptibility to BC and OC should include an epimutation screen.},
  language  = {en}
}